DJ-1 protects against neurodegeneration caused by focal cerebral ischemia and reperfusion in rats
DJ-1 protects against neurodegeneration caused by focal cerebral ischemia and reperfusion in rats
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DOI：
10.1038/sj.jcbfm.9600553
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发表时间：
2008-03-01
影响因子：
6.3
通讯作者：
Ariga, Hiroyoshi
中科院分区：
文献类型：
--
作者：
Yanagisawa, Daijiro;Kitamura, Yoshihisa;Ariga, Hiroyoshi
脑缺血和再灌注后，大脑中大量产生活性氧（ROS）。它与细胞成分发生强烈反应，产生有害影响并导致神经元细胞死亡。 DJ-1被发现是家族性帕金森病PARK7的致病基因，它是一种多功能蛋白，在转录调控中发挥关键作用，也是分子伴侣。在这项研究中，我们研究了 DJ-1 对缺血/再灌注损伤引起的神经退行性变的神经保护作用。使用腔内引入方法通过 120 分钟的大脑中动脉闭塞 (MCAO) 诱导大鼠脑缺血。 MCAO后3天，在2,3,5-氯化三苯基四唑染色中，纹状体内注射重组谷胱甘肽S-转移酶标记的人DJ-1 (GST-DJ-1)显着减少了梗死面积。此外，我们使用磁共振成像对缺血面积进行了无创评估，发现施用 GST-DJ-1 后梗塞面积显着减小。在 GST-DJ-1 治疗的大鼠中，行为功能障碍和硝基酪氨酸的形成均受到显着抑制。此外，GST-DJ-1 显着抑制 SH-SY5Y 细胞中 H2O2 介导的 ROS 产生。这些结果表明，GST-DJ-1 通过减少 ROS 介导的神经元损伤发挥神经保护作用，表明 DJ-1 可能是缺血性神经变性的有用治疗靶点。
Reactive oxygen species (ROS) is massively produced in the brain after cerebral ischemia and reperfusion. It reacts strongly with cellular components, which has detrimental effects and leads to neuronal cell death. DJ-1, which was found to be the causative gene of familial Parkinson's disease PARK7, is a multifunction protein, which plays a key role in transcriptional regulation, and a molecular chaperone. In this study, we investigated the neuroprotective effect of DJ-1 against neurodegeneration caused by ischemia/reperfusion injury. Cerebral ischemia was induced in rats by 120 mins of middle cerebral artery occlusion (MCAO) using an intraluminal introduction method. The intrastriatal injection of recombinant glutathione S-transferase-tagged human DJ-1 (GST-DJ-1) markedly reduced infarct size in 2,3,5-triphenyltetrazolium chloride staining at 3 days after MCAO. In addition, we performed a noninvasive evaluation of ischemic size using magnetic resonance imaging and found a significant reduction of infarct size with the administration of GST-DJ-1. In GST-DJ-1-treated rats, behavioral dysfunction and nitrotyrosine formation were significantly inhibited. Furthermore, GST-DJ-1 markedly inhibited H2O2-mediated ROS production in SH-SY5Y cells. These results indicate that GST-DJ-1 exerts a neuroprotective effect by reducing ROS-mediated neuronal injury, suggesting that DJ-1 may be a useful therapeutic target for ischemic neurodegeneration.